Meningeal leukemia—control versus cure

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Control of meningeal leukemia has been an important factor in the improved survival of children with acute lymphocytic leukemia (ALL). Major centers now report actual and projected leukemia-free 5-year survival rates of 50-70% following combined modality programs incorporating specific central nervous system (CNS) therapy.4.” The importance of meningeal involvement in ALL became progressively apparent with the increased success of systemic chemotherapy in inducing and maintaining hematologic remissions. Complete remission was terminated by primary CNS failure in 33-67% of patients who did not receive specific meningeal therapy.h.9 Meningeal relapse remains a threat even beyond conclusion of treatment. The group at St. Jude Children’s Research Hospital reported that 5 of 8 patients without CNS therapy demonstrated late meningeal relapse following cessation of chemotherapy.h The tragedy of such failure lies in our inability to control overt meningeal leukemia. The single most common cause of secondary failure in patients who are treated for meningeal relapse is repeated CNS invo1vement.i.h.‘5 Even with early diagnosis of asymptomatic meningeal relapse by cerebrospinal fluid (CSF) cytology, long term survival has been achieved in only 11 of 33 patients who received therapeutic craniospinal irradiation (CSI) at St. Jude (written communication, J. Simone, August 1976). Four of these 11 patients later required repeated CNS therapy for further episodes of meningeal failure after initial CNS relapse. While more optimistic results employing CSI and intrathecal methotrexate (IT-MTX) for overt meningeal leukemia have been reported from the Medical Research Council in England, few patients remain leukemia-free for significant periods after demonstrated CNS relapse.” Appreciating both the frequency and portent of meningeal relapse, in 1962 the group at St. Jude began a series of studies combining various chemotherapeutic regimens with specific anti-meningeal leukemia therapy early during remission. Although a stili impressive 17% of patients in their earlier studies remained free of leukemia, the incidence of primary CNS relapse was unaltered by delivery of 500-1200 rad in l-l.5 weeks CSI. Later studies, however, demonstrated a marked reduction in overt meningeal leukemia during hematologic remission (from 40-67% to 4-8%) using 2400 rad crania1 irradiation (CrI) with concomitant IT-MTX or a similar dose of CSI alone.h These results were confirmed by a Medical Research Council study in which only one of 75 patients developed primary meningeal relapse following CSI and IT-MTX.9 At the Joint Center for Radiation Therapy in Boston, none of 65 patients have had initial meningeal relapse following CrI and repeated doses of IT-MTX.4 Methods of meningeal treatment have included CSI, CrI or CSI with IT-MTX, and IT-MTX alone. Histopathologic studies of leukemic involvement in the meninges provide ample reason for not considering intrathecal chemotherapy alone.“’ Infiltrates in the deeper, perivascular arachnoid are not likely to receive adequate exposure to such medication. Clinical trials appear to support this contention. Investigators at the Hopital St. Louis, Paris, noted a 33% primary meningeal relapse rate despite repeated instillations of IT-MTX alone.’ Recent comparative studies